The present invention relates to a direct transition metal catalyzed process for the preparation of a variety of multifunctional substituted N-aminoindoles of formula I from 2-halo-phenylacetylenes or (2-sulfonato)phenylacetylenes and N,N-disubstituted hydrazines.
The Indole skeleton is found in numerous natural products as well as in the essential amino acid tryptophan and thus also in proteins. Indole derivatives display a vide variety of biological activities and can thus be regarded as a privileged structure in pharmaceutical research.
The ability of the indole scaffold to mediate an interaction with a variety of biological targets, is well-documented by a number of reports on the observed biological activity, as well as by the fact that many marketed drugs contain this heterocycle (J. A. Joule, in Science of Synthesis 2000, 10, 361ff and references therein). Examples of marketed drugs having an indole structural element include the anti-inflammatory indomethacin, the betablocker pindolol, the antimigraine agent sumitriptan and the 5-HT3 antagonist ondansetron.
Of course the use of indoles or azaindoles is not limited to the above-mentioned pharmaceutical application and it is well known that indoles can be useful in numerous other applications. For example, 1H-indole-3-acetic acid is used as a plant growth regulator and 3-methyl-indole (skatol) and various other indoles are used as components in perfumes and fragrances. Also N-aminoindoles display various biological activities such as antidepressant (F. Schatz, U. Jahn, T. Wagner-Jauregg, L. Zimgibl, K. Thiele Arzneimittelforschung 1980, 30, 919-23), analgesic (U.S. Pat. No. 4,983,608), acetylcholinesterase inhibition (Klein et. al. J. Med. Chem. 1996, 39, 570-581), thrombin inhibition (J. J. Cui et al. Bioorg. Med. Chem, Lett. 2002, 12, 2925-2930) and Ca2+-activated K+ channel opening (S. Hu, C. A. Fink, H. S. Kim, R. W. Lappe Drug. Dev. Res. 1997, 41, 10) among others. Furthermore, several compounds are actively being developed as drugs e.g. Nerispirdine (WO 2005097199).
Due to the interesting physical and biological properties of indoles a large number of syntheses for their formation have been developed, but most protocols are multistep procedures performed under harsh conditions, but also milder transition metal catalyzed protocols have been described (G. R. Humprey, J. T. Kuethe Chem. Rev. 2006, 105, 2875-2911). Among the existing transition metal catalyzed indole syntheses only a few examples employs the coupling between amines and 2-halo-phenylacetylenes followed by subsequent cyclization (T. Konno, J. Chae, T. Ishihara, H. Yamanaka J. Org. Chem. 2004, 24, 8258-8265; J. Chae, T. Konno, T. Ishihara, H. Yamanaka Chem. Lett. 2004, 33, 314-315; L. Ackermann Org. lett. 2005, 7, 439-442; L. T. Kaspar, L. Ackermann Tetrahedron 2005, 61, 11311-11316) but no examples using hydrazines have been reported.
The absence of an efficient synthetic protocol for the formation of indoles and N-aminoindoles from easily available 2-halo-phenylacetylenes and hydrazines clearly demonstrates a lack of synthetic methodology, thereby hindering the synthesis and optimization of important compounds such as a potential drug substance or other compound with desired properties. Thus, the present invention can for example be useful in preparing intermediates or end products of biologically active compounds in pharmaceutical and agricultural applications.